TW200529854A - Salt forms of 4-(4-methylpiperazin-1-ylmethyl)-n-[4-methyl-3-(4-pyridin-3-yl)pyrimidin-2-ylamino)phenyl]-benzamide - Google Patents

Abstract

The present invention relates to acid addition salts of 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, which are selected from the group consisting of a tartrate salt, such as a (D)(-) tartrate salt or a (L)(+) tartrate salt, a hydrochloride salt, a citrate salt, a malate salt, a fumarate salt, a succinate salt, a benzoate salt, a benzenesulfonate salt, a pamoate salt, a formate salt, a malonate salt, a 1,5-naphthalenedisulfonate salt, a salicylate salt, a cyclohexanesulfamate salt, a lactate salt, a mandelate salt, aq glutarate salt, an adipate salt, a squarate salt, a vanillate salt, an oxaloacetate salt, an ascorbate salt and a sulfate salt.

Description

200529854 IX. Description of the invention: [Technical field to which the invention belongs] • The present invention relates to 4-[(4-fluorenyl-1-hexahydropiperazinyl) methyl] -N- [4-fluorenyl, -3- [[4- (3-pyridyl) _2_pyrimidinyl] amino] phenyl] -benzidine is a salt form of a pharmaceutically active compound. [Prior art] 4-[(4-methyl-1-hexahydrosulfonyl) fluorenyl] -N- [4-methyl-3-[[4- (3-pyridyl) ) -2-Pyrimidinyl] amino] phenylbenzyl ® amines are known to the general public by their INN names and domains (plus domains). The domain and its manufacturing method are described in U.S. Patent No. 5,521,184. Basic pharmaceutically active compounds are usually formulated as pharmaceutical preparations in the form of an acid addition salt (especially a crystalline acid addition salt). For example, the mono-methane sulfonate is marketed in many countries under the trademark GLIVC or GLEEVEC. The two crystalline forms of the carboxymethylsulfenyl salt are described in side 99/03854. The crystal system named 0 is described by its physical properties. It is conducive to solid oral pharmaceutical dosage forms (such as lozenges and capsules). [Summary of the Invention]: Natural salt forms can improve the testability. The medicine has living physical or pharmacological properties. # 属 加 ,, M ^ can have advantages for a particular purpose before ... it is impossible to predict what kind of salt form and characterization of its salt form. According to the present invention, the non-additive domains of the non-additive domains are related to non-additive domains, which are helpful for solid or liquid formulations, especially solid oral dosage forms (^ "Zi Zhi's uniform like tincture tablets" And capsules) and> 99198.doc 200529854 = nocturnal form (such as: solutions and suspensions for administration), suppositories and other medicated dosage forms. Each of these salt forms has its own use Comes as a pesticide with active ingredients that can have one or more advantages. Characteristics = To easily make-or-more than one dosage form, improve stability! = The physical properties of bioavailability, and other Such properties are known to those skilled in the art. Κ, the salt form of the domain is prepared by a method known in the art for the preparation of amine acid addition salts, such as osmium or-appropriate anion exchange reagent treatment to add = The domains or domains solutions are usually combined with a solution of organic or mineral acids dissolved in, for example, lower alcohols (such as scallion or ethanol), which can be heated or unheated. Crystals or solvents evaporate Way to separate the salt, and ° as If necessary, the salt can be purified by recrystallization from an appropriate recrystallization solvent using a method known to those skilled in the art. For permeation of an oral solution, up to 4 doses for methyl; 6 Puff methyl] -N- [4_methyl_3 _ [[4_ (3_pyridyl) _2_pyrimidinyl] amino] phenyl] benzamidine salt 'purpose usually these salts It is preferred that the salt has a higher water solubility than the free base. 4 A salt with a lower water solubility than a salt with a lower water solubility generally makes it more suitable than a free salt for making a durable release. [Embodiment] The important specific embodiments of the present invention include 4 _ [(4_methyl small six odor odoryl) methyl + group] · N- [4-fluorenyl_3 _ [[4- (3_p [Methenyl] amino] benzyl] -benzidine salt is selected from the group consisting of tartrate (such as (D) tartaric acid or (L) tartaric acid), hydrochloride, citrate, Malate Heart 99198.doc 200529854 is D-malate), fumarate, succinate, benzoate, benzenesulfonate, paraben, formate, propane Diacid, 丨, 5-Disulfonic acid , Salicylate, cyclohexaneaminosulfonate, lactate (especially (s) _lactate), mandelate (especially (R) (-) mandelate), glutarate, A group consisting of adipic acid salt, dihydroxycyclobutenedione salt, vanillate, oxaloacetate, ascorbate (especially (L) _ascorbate) and sulfate. Other important aspects of the present invention Specific examples include adding ascorbate, domain formate, domain malonate, domain oxadiazone acetate, domain dicyclobutenedione salt, and domain vanillate. In a preferred embodiment, the acid addition salt is selected from the group consisting of tartrate (such as (D) (·) tartrate or (L) (+) tartrate), hydrogenate ', citrate, apple (Especially!) _ Malate), fumarate, succinate, benzoate, benzenesulfonate, bishydroxybenzoate, hemiformate, malonate Salt, salicylate, cyclohexaneaminosulfonate, mandelate (especially (R) (_) mandelate), hemiglutarate, adipate, vanillate The group consisting of sulfates. In yet another preferred embodiment of the present invention, the acid addition salt is selected from the group consisting of domain D- / ocherite, domain & malate, domain hemiformate, and domain malonate , Add domain salicylate, add domain glutarate, add domain cyclohexaneaminosulfonate, add domain mandelate (especially add domain (R) ㈠mandelate, add domain adipic acid The salt is a group consisting of domain vanillate and domain sulfate. The present invention further relates to a pharmaceutical composition comprising one of the above-mentioned domain salts and a pharmaceutically acceptable carrier. 99198.doc 200529854 a In a specific embodiment, the present invention relates to a pharmaceutical composition comprising a pharmaceutically acceptable carrier and 4-[(4-methyl-1-hexahydropiperazinyl) methyl] [4-methyl-3 -[[4- (3-p 比 pyridyl) -2-pyrimidinyl] amino] phenyl] -benzamide is an acid addition salt selected from the group consisting of tartrate (like (D) (_) tartaric acid Salt or (L) (+) tartrate), hydrochloride, citrate, malate (especially D-malate), fumarate, succinate, stearic acid , Benzoate xanthate, dihydroxyarsonate, formate, malonate, l55-arson disulfonate, salicylate, cyclohexaneaminosulfonate, lactate (especially Lactate), mandelate (especially (R) (_) mandelate), hydrous glutarate, adipic acid, dihydroxycyclobutenedione, vanillate, oxaloacetate , Ascorbate (especially (L) _ascorbate) and sulfate. In an important embodiment, the acid addition salt is selected from the group consisting of ascorbate, domain formate, and domain C. The di-acid salt is composed of citronella acetate, cis-dihydroxycyclobutadione salt, and cis-vanillic acid salt. The present invention also relates to a method for treating warm-blooded animals suffering from tumor diseases, in which administration requires such treatment (Especially gliomas, Indian nest tumors, prostate tumors' gastrointestinal stromal tumors, colorectal tumors, and lung tumors, especially small cell lung cancer, and chest tumors or other gynecological tumors, especially = leukemia treatment) A certain amount of warm-blooded animals Hydroxyl) methyl] Example 4. Methyl_3 _ [[4_ (3 'Mouth, /, Mofu 1xiao ψproduced soil selected σ 疋 group] amino group] native] the acid addition The diseases that are worrying about salt, especially ... are effective against the effects of dandan, # force effect, especially-inhibitory effect. Depending on race 'age, individual physical conditions, administration methods, and 99198.doc 200529854 The clinical signs discussed depend on the 'weight of about 70 kg: dose example ^ about daily dose of heart _ mg, preferably nourishing mg', especially 50-800 mg. Another aspect of the present invention is related to as claimed 4 ^ (4-diyl + hexahydrozinyl) methyl] of any one of 1 to 4] 1 [Hexymethyl-3-[[4- (3Lingyl > 2Lingyl] amino)] Phenyl] _phenylammonium acid plus & salt for use in the manufacture of a pharmaceutical composition which can be used to treat tumor diseases, especially glioma, ovarian tumor, prostate tumor, gastrointestinal stromal tumor Colorectal tumors, and lung tumors, especially small cell lung cancer, and chest tumors or other gynecological tumors, especially leukemia. The following examples are intended to illustrate the invention, but not to limit its scope. Example 1 4 _ [(4_methyl · 1_hexahydropiperazinyl) methyl] 丨 -methyl_3 _ [[4 (3'pyridyl) _2-pyrimidinyl] amino] phenylbenzidine Amine, tartrate will be methyl hexahydroxazinyl) methyl] -N- [4-methyl | [[4- (3-exo b • adenyl) 2-pyrimidinyl] amino] phenyl]- Benzamidine (4.94 g, 10 mmol) 1 into (2R, 3R) _2,3_dihydroxybutanedihydrazone (L (+) _ tartaric acid, dissolved in hot ethanol (40 ml)), Fluka, Rutsch, Switzerland; 50 g / millimol). The solution was evaporated to dryness under reduced pressure, and the residue was recrystallized from methanol. After filtration and drying, a light yellow crystalline solid 4 [(4-methyl _; [_ hexahydropiperazinyl) methyl Group] · Ν_ [4_methyl • pyridine) 2 in σ 疋 group] yynyl] benzyl] _benzidine, a tartrate salt, has the following analytic properties: 6〇18; Η, 5.96; N, M · 86〇 / 〇; Η20, 2.25%. The calculated values for C33H37N7〇7-〇 · 82 H2 ft are ·· c, 99198.doc 10 200529854 60.19; H, 5.91; N, 14.89; H20, 2.24%. Example 2 4-[(4-methyl-1_hexahydropiperazinyl) methyl] · N_ [4_methyl_3_ 丨 [4… pyridylpyrimidinyl] amino] phenylbenzophenazine Amine, hydroacid. Aqueous hydrochloric acid (0.99 g, 37 ° / 〇) was added to 4-[(4-methyl- small hexahydroxazinyl) methyl] _N_ [4 dissolved in ethanol (20 ml). _Methylpyridyl) _2-pyrimidinyl] amino] phenyl] -benzidine (4 94 g, 10 mmol). The solution was evaporated to dryness under reduced pressure, and the resulting residue was crystallized from ethanol · ethyl acetate. The product was transitioned and recrystallized from isopropanol (after hydrazone and drying) 'to give a 4-y-4-ylhexahydrofluorenylmethyl group as a pale yellow crystalline solid] · N- [4 · methyl -Η [Μ3- 料 基] -2-fluorenyl] amino] phenyl] -benzidine, hydrochloride, has the following analytical properties: experimental analytical value. C, 65.27; hydrazone, 6.07 ; Ν, 18.19; C1, 6.55%; Η20, 0.56 0 / 〇. For C29H32N7〇C1. 0.17 η2〇, the calculated values are: c, 65 · 33; & 6.η, N, 18.39; C1, 6.65%; η20, 0.57%. Example 3 4 [[Methylmethylhexahexamethylene] methyl] [[m] [[4 · Feridyl] 2pyrimidyl] amino] phenylphenylbenzidine, citrate to / Huangxia, will be [[4-methylhexahydropiperazinyl) fluorenyl] -N- [4-fluorenyl than sulfanyl) · 2 ♦ amidyl] amino] phenyl] -benzylamine ( 4% g, 10 mmol), anhydrous 2-hydroxy-U2 dissolved in methanol (30 ml),% propionate: hydrazone-like acid; Merck, Da, brd · '192 g, 1 〇mmole)> Valley fluid. Upon cooling, 4 _ [(4_fluorenyl4-hexahydrogenyl) fluorenyl] oxo [4-fluorenyl_3 · [[4 · (3_ρ 比 pyridyl) _2_mouth pyridyl] amine ] 99198.doc 200529854

Phenyl] -benzamide, citrate. A pale yellow crystalline solid was obtained after filtration and drying, with the following analytical properties: experimental analytical values: C, 59.24; H, 5.71, N, 13.60%, H2O, 2.14%. For C35H39N7O8-0.83 H2O • the calculated values are: C, 60.00; H, 5.85; N, 13.99%; H2O, 2.13%. Example 4 4-[(4-methyl-1-hexahydrocarbamidinyl) methyl N_ [4-methyl-3-[[4- (3_erimidinyl) -2_pyrimidinyl] amino ] Phenyl] -benzylamine, malate ί 4-[(4-methyl-1-hexahydropiperazinyl) methyl] fluorene_ [4_fluorenyl-3-[[4- ( 3-pyridyl) -2-pyridyl] amino] phenyl] -benzidine (4.94 g, 10 mmol) was added to (2S)-(· ) · Hydroxybutanedioic acid (L-(-) · Hydroxysuccinic acid; Fluka, Buchs, Switzerland; 34 g, 10 mmol). The mixture was heated and the resulting hot solution was filtered, and the hot solution was evaporated to dryness under reduced pressure to obtain a residue recrystallized from ethanol. After filtration and drying, a light yellow crystalline solid 4 · [(4 • Methyl_ 丨 _Hexane_Chenqinyl) Methylbutanyl N_ [4-methyl-H [4- (3-Hydroxybenzyl) · 2 "Dense group] Amine] Phenyl] -benzene Phenamine'malate has the following analytical properties: experimental analytical value · C, 62.88, hydrazone, 6.04; N, 15.60%; η2〇, 0.45%. For C33H37N7〇6 0.16 H2〇 ^ a tf ^: c, 62.86; H5 5.97; N? 15.55%; • H20, 0.46%. • Example 5 4 [(4-methyl-1-hexahydrocarbazinyl) methyl] | [4methyl ^ [[ Heart (3 pyridinyl A fluorenyl) amine] phenylbenzamide, fumarate will be (trans > butanedioic acid (fumarate; Fluka, Buchs, Switzerland; 99198.doc -12- 200529854 1_16 g, 10 mmoles) and 4 _ [(4-methyl · hexafluoroazinyl) methyl] -N- [4-methyl dissolved in ethanol (25 ml) Of 3--3-[[4- (3.pyridyl) -2-pyrimidinyl] amino] phenylbenzamide (4.94 g, 10 mmol) The mixture was heated to 90 C, treated with water (18 g) and filtered. The product crystallized out upon cooling and was filtered and dried to give a pale yellow crystalline solid 4 _ [(4_methyl · buhexahydro Xylazinyl) methyl] _N- [4-methyl-3 · [[4- (3-pyridyl) -2-pyrimidinyl] amino] phenyl] -benzamide, fumarate Salt has the following analytical properties: Persistent analysis value: C, 63.91; H, 5.99; N, 15.74%, H20, 1.27%. The calculated value for C33H35N705-0.44 H20: c, 64.18; H, 5.86; N, 15.88%; H205 1.28%. Example 6 M (4-fluorenyl · 1-hexahydropiperazinyl) methyl N- [4-fluorenyl-3] [4- (3-pyridine ) -2-, fluorenyl] amino] phenylbenzamidine, succinate 4-[(4-methyl-1-hexahydropiperazinyl) fluorenyl;] _ N_Bulfyl- 3 VII 4_ (3_pyridine 11 fluorenyl) -2 -pentayl [amino] phenyl] phenyl] -benzidine (494 g, 10 mmol) Butyl dissolved in ethanol (25 ml) In a solution of mandelic acid (succinic acid; Fluka, Buchs, Switzerland; 1.18 grams, 10 millimoles). The mixture was heated to 90 ° C. and treated with water (0.2 grams) and Filter. The product crystallizes upon cooling. After filtering and drying, a light yellow crystalline solid 4-[(4-fluorenyl-1 -hexahydroazinyl) fluorenyl] -N- [4-methyl- 3-[[4- (3-pyridyl) -2-pyrimidinyl] amino] phenyl l · benzidineamine'succinate, having the following analytical properties ·· Experimental analytical values · c, 64.19; H , 6.11; N, 15.82%; H20, 0.87%. The calculated values for C33H37N705-0.30H20 are: C, 64.23; H, 6.14; N, 15.89%; H2O, 0.88%. 99198.doc -13- 200529854 Example 7 4-[(4-methyl_1_hexahydropiperazinyl) methyl] _N- 丨 'methyl [丨 4 (3pyridyl) -2_pyrimidinyl] amine Iphenylphenylbenzamide, benzoate will be 4-[(4-methyl-1-hexahydropiperazinyl) methyl] · [心 methyl_3-[[4_ (3 ^ 比(Pyridyl) -2-pyrimidinyl] amino] phenyl] -benzidine (4.94 g, 10 mmol) benzoic acid (Fluka, Buchs, Switzerland; 1.2 g, 10 mol). The mixture was heated and the resulting hot solution was transitioned. The product crystallized upon cooling, and a light brown crystalline solid was obtained after filtration and drying. 4-[(4-fluorenyl-1-hexahydropiperazinyl) methyl 1 ^ [4_methyl-3- [ [4- (3-pyridyl) _2_pyrimidinyl] amino] phenylbenzimidamine, benzoate, has the following analytical properties: Experimental analysis value: c, 7〇13; H, 612; N , 16.24. /. . The calculated value for C36H37N7〇3 is: C, 702; H, 6.06; N, 15.92%. Example 9 4-[(4-methyl-1 · hexahydropiperazinyl) methyl 'Methyl 丨 丨 4 (3-pyridyl) -2-pyrimidinyl] amino I phenylbenzamidine, benzenesulfonate will be 4-[(cardiomethyl_1_hexahydropiperazinyl) Methyl] -N_ [4_methyl_3 _ [[4-Gas 3-pyridyl) -2-pyrimidinyl] amino] phenyl > benzamidine (4.94 g, 10 mmol) To a solution of benzenesulfonic acid (Fluka, Buchs, Switzerland; 1.61 g, 1 G millimolar) in hot toluene (40 ml) was added. The solution was evaporated to dryness under reduced pressure, and the resulting residue was recrystallized from ethanol-ethyl acetate. The product was filtered and dried to obtain a light yellow crystalline solid heart [(Heartylmethylhexahexamethylene) methyl; | -Ν- [4-methyl-3-[[4- (3- 口Specific octyl) -2 ♦ Amine] Amine] phenylbenzidinecarboxamide, benzoxanthanate, has the following analytical properties ···, experimental analytical values · c 99198.doc -14- 200529854 64 · 19; Thallium, 5.68; N, 14.93; S, 4.87%; h20, 0.34%. For C35H37N704S-0 · 12 H2〇, the calculated values are: c, 64 28; η, 5.74; N, 14.99; S, 4.90%; Η2, 0.33%. Example 10 4-[(4-Methylhexahexazinyl) methyl] _N 丨 4methyl_3 [丨 4 Benzyl] -2_Dimethyl] amino] phenyl] _benzene Methylamine, MH (cardiomethyl + hexamethylol) methyl dissolved in ethanol (50 ml) with thermyl formate heated by double theophylformate]-: ^ 4. ] Amine] phenyl] benzidine (4.94 g, 10 mmol) and 4,4, -amidinobis [3_hydroxy_2_fluorenic acid (Fluka, Buchs, Switzerland; 3.88 G, 10 mmol). Then add water (25 ml). The product crystallized upon cooling, and the product was filtered and dried to obtain 4-[(4-methylhexahydropiperazinyl) methyl] -N- [4-methyl_3-[[ 4- (3-Pyridinyl) -2-pyrimidinyl] amino] phenylbenzamide, a dihydroxyarsonate, has the following analytical properties: Experimental analytical value: C, 69.12; Hf, 5.62 N, 10.88%; H20.50%. The calculated values for C52H47N7〇7 are: C, 69.04; H, 5.52; N, 10.84%; H2O, 2.51%. Example 11 4- 丨 (4-Methyl-1-hexahydropiperazinyl) fluorenyl N- [4-methyl_3-[[4- (3_pyridyl) -2-pyrimidinyl] amino ] Phenylbenzidine, salicylate solution of 2-hydroxybenzoic acid (salicylic acid, Fluka, Buchs, Switzerland; 558 mg, 4 mmol) in ethanol (50 ml) Add 4-[(4-methyl-1-hexahydropiperazinyl) methyl] -N- [4-fluorenyl-3-[[4- (3-pyridyl) -2-pyrimidinyl] amino] phenyl] -benzimidamine 99198.doc 15 200529854 (1.975 g, 4 mol). 90. Under the conditions of 0 and 400 mbar, the volume of the hot solution was reduced to 80 ml by rotating the thermal hair, and then it was slowly cooled to 20 C. After filtration and drying, a crystalline solid 4 _ [(4_methyl _ 丨 _Hexahydrozinyl) methyl] -N- [4-methyl-3 · [[4_ (3 ♦ Amino) · 2_pentayl] Amine] phenyl] -methaneformamide ' Salicylate 'has the following analytical properties: experimental analytical values: C, 68.18, H, 5.93; N, 15.52; 〇, 10.42%. H20, 0.31%. The calculated value for 〇: 3611, 〇4-〇.U ho: c, ".η; h, 5.92; N, 15.47; 〇, 10.38%. h2〇, 〇 31%. Example 12 M (4 · methyl-1-hexahydrocarbazinyl) methyl] _N_ [4methyl_3 _ [[4 (3eryl) -2_pyrimidinyl] amino] phenyl] _benzene Methylamine, vanillate. A solution of 4-hydroxy-3-methoxybenzoic acid (vanillic acid, Fluka, Buchs, Switzerland; 694 mg, 4 mmol) in ethanol (50 ml) was added. 4-Methylmethylhexahexafluorenyl) dissolved in hot ethanol (150ml under 9th generation) methyl] N [4methyl-3-[[4- (3-E. Amidinyl) _2_pyridinyl ] Amine] phenyl] -benzamide (1.975 g '4 mmol) in solution. The solution was evaporated to dryness under reduced pressure and the resulting residue was recrystallized from ethanol. The product was transitioned and dried to obtain a crystalline solid 4 _ [(4 • methylpentahexafluorenyl) methyl] -N- [4-methyl-3-[[4 · (3 · ρbipyridyl) _2_Methylpyridyl] amino] phenylbenzamide, vanillate, has the following analytical properties: experimental analytical values: c, 66.61; hydrazone, 6.18; N, 14.74; 〇, 12 86%. ^ 〇, ο ,. . The calculated value for C37H39N705-0.3i Η2〇 is: c, ^ 59; & $ 98; N, 14.69; 0, 12.73〇 / 〇. η20, 0.84%. '' Example 13 99198.doc -16- 200529854 4-[(4-methyl-1-hexahydropiperazinyl) methyl group ... 丨 methyl methyl winter 丨 丨 4 (3pyridyl) -2-yl ] Amine] Phenyl] -benzamide, cyclohexaneamine salt • N-cyclohexylaminosulfonic acid (Fluka, • Buchs, Switzerland; 732 mg) to be dissolved in ethanol (100 ml) , 4 mmol) was added to 4-[(4-methyl-hexahydropiperazinyl) fluorenyl [heart methyl-3-[[4 -(3-pyridyl) -2-pyrimidinyl] amino] phenyl] -benzamide (1.9 to 5 g, 4 mmol). The solution was evaporated to dryness under reduced pressure, and the resulting residue was recrystallized from ethanol-isopropanol. The product was filtered and dried to obtain 4-[(4 · fluorenyl + hexahydropiperazinyl) methyl] _N- [4-methyl-3-[[心 (3- 说) -2 "melidinyl] amino] phenyl > benzamidine, cyclohexaneamine sulfonate, has the following analytical properties: experimental analysis value: C, 61 · 13; Η, 6.75; Ν, 15.87; 〇, 11.80; S, 4.57%. H20, 1.69%. Calculated value for CnHLuNsCUS-0.40 isopropanol · 0.70h2〇: C, 61.28; Η, 6 · 90; N, 15.79; 〇, 11.50; S, 4.52%. H2O, 1.78%. [[4 (3-erimidinyl) -2-pyrimidinyl] amino] phenylbenzamide, hemiglutarate will be dissolved in ethanol (60 ml) μ-glutaric acid (glutaric acid Acid; Fluka,

Buchs, Switzerland; A solution of 539 Hui Teng, Mao Jian 4 mol) was added to hot ethanol定 ° 基基) · 2-pyridyl j amine j phenyl] -benzidine (1. 75 g '4 mmol) in a solution of 9.0 and 400 mbar, The volume of the hot solution was reduced to 80 ml by rotating the solvent, and then slowly cooled 99198.doc -17- 200529854 to 20 C 'after filtration and drying to obtain a crystalline solid 4-[(4-methyl- Hexahydropiperazinyl) fluorenyl] -N- [4-fluorenyl-3-[[4- (3-pyridyl) -2-pyrimidinyl] amino] phenyl] -phenylhydrazine, half Glutamate has the following analytical properties: Experimental analytical values: C, 64.62; H, 5.81; N, 16_81; 0, 11.96%. H2O, 4_14%. Calculated value for C32H36N7〇3_ 1.5H2〇 C, 64.74; H, 6.62; N, 16.51; 〇, 12.13%. Η20, 4.55%. Example 15 4-[(4-fluorenyl-1-hexahydropiperazinyl) f-kibu ~ [4-Methyl ^ 4 (3pyridyl) _2_pyrimidinyl] Amine] Phenylbenzidine, malonate will be dissolved in ethanol (60ml) 丨A solution of 3-propanedioic acid (malonic acid; Fluka, Buchs, Switzerland; 420.5 mg, 4 mmol) was added to 4-[(4-methyl-1- Hexahydrobranyl) methyl N- [4-methyl-3-[[4- (3-pyridyl) -2_pyrimidinyl] amino] phenylbenzidine (1.975 g '4 mmol Ear) solution. The hot solution was slowly cooled to 20 ° C, filtered and dried to obtain a crystalline solid 4 _ [(4-methyl · hexahexapiperazinyl) methyl] -N- [4- Methylpyridyl) -2-pyrimidinyl] amino] phenyl l-phenylamidamine, malonate, has the following analytical properties: Experimental analytical value: C, 64 · 0; H, 6.1; N, 16.3 0, 13.6%. H20, < 0.3%. The calculated value for C32H35N705 is: C, 64 · 31; H, 5.90; N, 16 4〇; 0, 13.38% 〇 Example 16 4-[(4 · fluorenyl_1_hexahydropiperazinyl) methyl Glyph & 丨 'methyl 3 _ [[4-Gas 3_pyridinyl) _2_'Bentyl] amino] phenylbenzylamine, sulfate

A solution of sulfuric acid (Fluka, Buchs, Switzerland; [M 99198.doc -18- 200529854 4.0 ml]) dissolved in ethanol (50 ml) was added to 4 of the solution dissolved in hot ethanol (350 ml at 90 ° C). -[(4 · methyl-1-hexahydropiperazinyl) fluorenyl] · N_ [4-fluorenyl-3-[[4- (3-pyridyl) -2-, tetramethyl] amino] benzene Of phenyl] -benzamide (1.975 g, 4 mmol). The hot solution was slowly cooled to 20 t, filtered and dried to obtain a crystalline solid 4 _ [(4-methyl-1-hexahydropiperazinyl) fluorenyl] -N · [4-fluorenyl-3- [[4- (3-Pyridinylpyrimidinyl] amino] phenyl] -benzimidamine, sulfate, has the following analytical properties: Experimental analysis value: C, 55.17; H, 5.82; N, 15.57; 〇, 18.29%; S, 5.26%; H20, 5.89%. The calculated values for C29H33N705S-2.06 H20 are: C, 55.34; H, 5.95; N, 15.59; 0, 17.96%; S 5 · 10ο / 〇. H2O, 5.90%. Example 17 4-[(4-methyl-1-hexahydropiperazinyl) methyl] -N-['methyl ^ [[4 (3pyridyl)- 2-pyrimidinyl] amino] phenylbenzamide, adipic acid salt will be dissolved in ethanol (80 ml) ... Hexane diacid (adipic acid; Fluka, Buchs, Switzerland; 081 mg, 4 mmol) of 4 _ [(4_methyl_ι_hexahydroxazinyl) methyl] _N_ [4_methyl-3-[[ 4- (3-p specific pyridyl) _2_pyrimidinyl] amino] phenyl] -benzidine (1.975 g, 4 mmol) in a solution of 90.0 and 400 mbar Through rotary evaporation The volume of the hot solution was reduced to 80 ml, and then it was slowly cooled to 20 ° C. After filtration and drying, a crystalline solid 4 _ [(4 · methylhexahydrocenzinyl) methyl] -N- [ 4-Methyl [[Heart (30% than octyl) -2 "dense. Dingyl] Amine] Benzoite] Dimethanone monocaproate has the following analytical properties ·· Experimental analysis value · C, 64.97, H, 6.33; N, 15.44; 〇, 12.77%. H20, 1.43%. Calculated value for C35H41N7〇5-0.5 h2〇 · c, 64 · 76; H, 99198.doc -19- 200529854 6.53 'N, 15.10; 〇, 13.61%. H20, 1.44%. Example 18 4-[(4-methyl- small hexahydropiperazinyl) methyl] 4 丨 4methyl-3 _ [[4 ( 3pyridinyl) -2-pyrimidinyl] amino] phenyl] _benzidine, (R) _ (+ mandelate will be dissolved in ethanol (60 ml) of hydroxyphenylacetic acid ((D) _ (+ Mandelic acid; Fluka, Buchs, Switzerland; 553 mg, 3.13 mmol) was added to 4 _ [(4_methyl · 丨 _ Hexahydrofluorenyl) methyl] Example 4-methyl winters ... pyridinyl) _2_pyridinyl] amino] phenyl] -benzidine (1.975 g, 4 mmol) In solution. 90. . And 400 bar, the volume of the hot solution was reduced to 80 ml by rotary evaporation, and then slowly cooled to 2 (TC, filtered and dried to obtain a crystalline solid heart [(4-methyl small Hexahydrozinyl) methyl] _N_ [Cardiomethyl_3 _ [[4 _ (^ Aid) -2-pyrimidinyl] amino] phenylbenzidine, mandelate, has the following analytical properties: experimental analysis Value: C, 68.60; H, 6 27; N, 15 19; 9.91 / 〇. Η20 '〇 · 22〇 / 0. Calculated value for C37H39N704-〇 · 〇8 η2〇: C, 68 · 67; hydrazone, 6.10; N, 15.15; 〇, 10.09%. Η20, 〇22%. Example 19 '' [(4-methyl hexahydroxazinyl) methyl] Example 4m [[Cardimidyl] _2_pyrimidinyl] Amine] Phenylbenzidine, malate will be dissolved in ethanol (60 ml) of (2RM-l · hydroxybutane diacid ((D) _ Yunoic acid; Fluka, Buchs' Switzerland; 553 mg, 2.83 mmol.) Solution was added to 4 _ [(4_methyl_ 丨 · hexahydro] in hot ethanol (150 ml at 90t). Fluorenyl) methyl] Example 4-methyl_3 _ [[4_ (3_propenyl) ~ dense-bentyl] amino] benzyl] • benzidine ( 1.975 grams, 4 millimoles) in a solution of 9 (TC and 400 99198.doc -20- 200529854 under the house's volume by rotary evaporation to reduce the volume of the hot solution to 80 ml, and then slowly cool it to 20%. ° C, filtered and dried to obtain a crystalline solid M (4-methyl-1-hexahydropiperazinyl) methyl dipper methyl_3 _ [[4 · (3_pyridyl) -2-pyrimidine [Amino] amino] phenyl] -benzamide, malate, has the following analytical properties: · Experimental analytical values · C, 62.14; H, 6.33; N, 15.48; 0, 16 · 18%. H20, 1.99%. The calculated value for C33H37n7〇6 · 71 · 2h0 is ··· C, 61.88; Η, 6.05; N, 15.31; 0, 16.67%. Η20, 2.00%. Example 20 4 -[(4-methyl-small hexahydropiperazinyl) methyl] each ['methyl 1 [[4- (3 ^ pyridinyl) -2-'bitenyl] amine] phenylbenzyl Amine '(〇) _ (_) _ Tartaric acid will be dissolved in ethanol (90 ml) of (2S, 3S) _2,3dihydroxy-butanedicarboxylic acid (tartaric acid; Fluka, Buchs, Switzerland; 606.5 mg, 1.97 MM) solution was added to 4-[(4-methyl-1αhydroxazinyl) in hot ethanol (150 ml at 90 ° C) Yl] -N- [4- yl Yue _3 - [[4- (3-p ratio of π given yl) _2- densely populated. Amine] Amine] phenyl > A solution of benzamidine (1.975 g, 4 mmol). The hot solution was slowly cooled to 20 ° C, and filtered and dried to obtain a crystalline solid 4-[(4-methyl-1-hexahydropiperazinyl) methyl] -N- [4-methyl-3- [[4_ (3 • Pyridyl) -2-pyrimidyl stilbyl] amino] phenyl] -phenylhydrazone, a tartrate salt, has the following analytical properties: experimental analysis value: C, 60.54; hydrazone, 6.08; Ν, 14.37; 0, 18.89%. Η20, 1.32%. The calculated value for C3 3H37N7〇7-0.50 ethanol-0.50 η20 is · C, 60 · 43; H, 6.12; N, 14.51; 〇, 18.94% 〇 20, 1.33%. Example 21 4-[(4 · fluorenyl · 1-hexahydron-substituted fluorenyl) fluorenylmethyl-3 · [[4- (3-eryl) -2-pyrimidinyl] amino] phenyl]- Benzamidine, hemiformate 99198.doc -21-200529854 A solution of fs_uka, Buchs, Swiss mg, 8 millimoles in ethanol (20 ml) was added to hot ethanol (15 ml under thief) ) Of 4-[(4-methyl-1-hexahydro mouth mouth taste its flying spear, base) ▼ ylmethyl-3 _ [[4_ (3_pyridine earth 2-mouth in the octyl] amine group] Phenyl benzamidine (1.975 g, A millimolar) in the solution. The solution was evaporated to dryness at reduced I, and the residue was recrystallized from Chongcai: residue. The product was subjected to hydration and drying to obtain— Crystalline solid custom methyl-1-hexahydrozinyl) methyl] | [4_methyl-3 _ [[4〇 比比 基] · 2_Spray bite ^]

Amine] phenyl] -benzidine, hemiformate, has the following analytical properties: ^ Test analytical value: C, 68.50; Hf, 6.24; N, 18.93; 0, 6.43%. η20 1.69%. The calculated value for c ^ HwNmO4 · 18〇 ho is 68.46; H, 6.25; N, 18.95; 〇, 6.34%. Η2〇, 〇ιι〇〇 / 〇. Example 22_ Capsules contain 100 mg of 4-[(4-methyl-1-hexahydropiperazinyl) methyl] _N_ [4_methyl-3-[[4- (3-pyridyl) -2-pyrimidine [Amino] amino] phenyl] phenylbenzamine salt (,, salts,,) capsules are usually prepared with the following composition:

a Salt-forming 100 mg microcrystalline cellulose 200 mg PVPPXL 15 mg highly dispersed silicone 2 mg magnesium stearate 1.5 mg 318.5 mg These capsules are mixed with the ingredients and the mixture is filled in a hard formula 99198.doc -22- 200529854 Capsule (size υ) Preparation Example 23-Water Solubility

5 ψ group-1 · hexahydropiperazinyl) methyl] -NH at room temperature] Pridyl] " —, 7 Τ Φ Methyl * fluorenyl] amino] benzyl] -benzidine _ Solubility column In the table below: φ. For comparison, the free solubility at room temperature is 0.44 mg / ml. Bingoline in water

Table 1

99198.doc -23-

Claims (1)

200529854 10. Scope of patent application: 1. A 4 _ [(4-methyl_1_hexahydropiperazinyl) methyl] _N- [4_methyl-3-[[4- (3-pyridyl) _2 _Pyrimidinyl] amino] phenyl] -phenylhydrazine is an acid addition salt selected from tartrates (such as (D) (-) tartrate or (L) (+) · petrate), Hydrochloride, citrate, malate (especially d_malate), fumarate, succinate, benzoate, sulfonate, bishydroxybenzoate, Formate, malonate, 1,5-ammonium disulfonate, salicylate, cyclohexaneaminosulfonate, lactate (especially (s) _lactate), mandelate ( In particular (with (_) mandelate), hydrous glutarate, adipic acid, dihydroxycyclobutenedione salt, vanillate, oxaloacetate, ascorbate (especially (L) _ Ascorbate) and sulfate composition = Group 0 2. —An acid addition salt is selected from the group consisting of imatinib ascorbate, domain formate ', domain malonate, and domain acetic acid Salt, plus dicyclohexidine disulfide A group consisting of domain vanillates. 3. —Species 4-[(4-methyl small hexahydropiperazinyl) methyl] _n_ [4_methyl · 3 _ [[4- (3 · P 比Bentyl) -2_ ° Pyridyl] amino] phenyl] -benzidine acid: salt formation, selected from tartrate (such as (D) tartrate or (l) tartrate), hydrogen chloride Acid salt, citric acid, Tagutian said that M m is a salt of salt, fructrate (especially D_malate), butanedioic acid, butane-deficiency .. ^ butane-acid, Benzoate, benzenesulfonate, bishydroxybenzoate, hemiformate, two_post, l ^ mono-salt 'salicylate, cyclohexylamine contanoate, mandelate "Pulling W 拉 / ΤΪ, /, β 夂 (especially (R) ㈠ mandelate), hemiglutarate, adipate, citronella i ^ ^ early salt and sulfate group 99198.doc 200529854 4. Species addition salts are selected from the group consisting of domain D-tartrate, domain D_Ping, I salt 'plus domain hemiformate, domain malonate, and domain summer, Add domain glutarate, add domain cyclohexanoic acid, and add domain almond Acid salt (especially, j is a group consisting of domain (R) ㈠ mandelate, domain domain | undersalt, domain domain vanillate and domain sulfate. 5. A pharmaceutical composition comprising A pharmaceutically acceptable carrier and 4 g of methylhydropiperazinyl) methyl] _N_ [4 · methyl_3 _ [[4_ (3_pyridyl) _2_pyrimidinyl] amino] benzyl] _benzyl The acid addition salt of amidine is selected from the group consisting of tartrate (such as 疋 (D) (_) tartrate or (L) (+) tartrate) ", hydrochloride, citrate, malate (especially D- Malate), fumarate, butyl-benzylbenzate, benzoxanthanate, bimeneformate, formate, propanone, ι, 5-naphthalene Sulfonates, salicylates, cyclohexaneamine sulfonic acid, salicylates (especially (S) -lactate), mandelates (especially (R) (_) mandelate), hydrous A group of glutarate, adipate, dicyclobutanone, vanillate, oxaloacetate, ascorbate (especially (L) -ascorbate), and sulfate. 6. The pharmaceutical composition of claim 3, wherein the acid addition salt is selected from the group consisting of ascorbate, domain formate, domain malonate, and oxadiazine salt. A group consisting of hydroxycyclobutenedione salt and domain vanillate. 7 · -A kind of request is called the heart of any one of [[Heartylmethylhexahexamethyl] methyl] -N- [心 methylj [[心 (3 巧 比基基) _2 ♦ definite base] Amino] phenyl] _ benzamidine acid addition salt for use in the manufacture of a pharmaceutical composition, 99198.doc 200529854, especially for the treatment of leukemia, the pharmaceutical composition is used to treat tumor diseases0 99198.doc 200529854 7. Designated Representative Map: (I) The designated representative map in this case is: (none) (II) The component symbols of this representative map are simply explained: 8. If there is a chemical formula in this case, please disclose the chemical formula that best shows the characteristics of the invention: (none) 99198.doc